Excitatory-inhibitory(E/I)balance is essential for normal neural development,behavior and cognition.E/I imbalance leads to a variety of neurological disorders,such as autism and schizophrenia.NMDA receptors(NMDARs)reg...Excitatory-inhibitory(E/I)balance is essential for normal neural development,behavior and cognition.E/I imbalance leads to a variety of neurological disorders,such as autism and schizophrenia.NMDA receptors(NMDARs)regulate AMPAR-mediated excitatory and GABAAR-mediated inhibitory synaptic transmission,suggesting that NMDARs play an important role in the establishment and maintenance of the E/I balance.In this review,we briefly introduced NMDARs,AMPARs and GABAARs,summarized the current studies on E/I balance mediated by NMDARs,and discussed the current advances in NMDAR-mediated AMPAR and GABAAR development.Specifically,we analyzed the role of NMDAR subunits in the establishment and maintenance of E/I balance,which may provide new therapeutic strategies for the recovery of E/I imbalance in neurological disorders.展开更多
CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP o...CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.展开更多
基金the National Natural Science Foundation of China(Grant No.32170975)Guangdong Nature Science Foundation(Grant No.2019A1515011309).
文摘Excitatory-inhibitory(E/I)balance is essential for normal neural development,behavior and cognition.E/I imbalance leads to a variety of neurological disorders,such as autism and schizophrenia.NMDA receptors(NMDARs)regulate AMPAR-mediated excitatory and GABAAR-mediated inhibitory synaptic transmission,suggesting that NMDARs play an important role in the establishment and maintenance of the E/I balance.In this review,we briefly introduced NMDARs,AMPARs and GABAARs,summarized the current studies on E/I balance mediated by NMDARs,and discussed the current advances in NMDAR-mediated AMPAR and GABAAR development.Specifically,we analyzed the role of NMDAR subunits in the establishment and maintenance of E/I balance,which may provide new therapeutic strategies for the recovery of E/I imbalance in neurological disorders.
基金supported by the National Natural Science Foundation of China(No.30670680)the Medical Foundation for younger scholars of Xi'an Jiaotong University(No.YQN0811)
文摘晚时相长时程增强(late-phase long-term potentiation,L-LTP)对于海马长期记忆的维持具有非常重要的作用,然而L-LTP可被诱导之后的神经元活动所翻转。本实验旨在研究海马CA1区L-LTP的翻转是否有突触前机制的参与以及L-LTP翻转前后AMPARs的表达有无变化。实验采用海马脑薄片细胞外场电位记录技术,使用强直刺激(high-frequency stimulation,HFS)诱导出CA1区L-LTP,2h后用两组间隔10min的高强度的双脉冲低频刺激(high-intensity paired-pulse low frequency stimulation,HI-PP-LFS)诱导L-LTP翻转。在LTP诱导前、诱导2h后、翻转后均给予一个双脉冲刺激,观察双脉冲比值(paired-pulse ratio,PPR)的变化;另一方面,实验通过免疫荧光组织化学方法观察AMPAR/GluR2在L-LTP翻转前后海马CA1区表达的变化。结果显示,L-LTP诱导后2h,HI-PP-LFS可诱导L-LTP的部分翻转(翻转率为61.79%±14.51%)。LTP诱导前、诱导2h后、翻转后PPR均大于1,表现为双脉冲易化(paired-pulse facilitation,PPF),且三者大小顺序为:LTP诱导后<LTP翻转后<LTP诱导前;在海马CA1区AMPAR/GluR2亚单位的表达方面,对照组、LTP组及LTP翻转组之间没有显著差异。上述结果提示,海马CA1区L-LTP维持与翻转均有突触前机制的参与,但L-LTP诱导与翻转前后AMPAR/GluR2表达没有发生变化。
基金This work was supported by Science and Technology Innovation 2030-Major Project(2021ZD0203501)the National Natural Science Foundation of China(81930030,31771109,and 31722023)+5 种基金the National Key R&D Program of China(2019YFA0508603)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-057)Project for Hangzhou Medical Disciplines of ExcellenceKey Project for Hangzhou Medical Disciplinesthe Fundamental Research Funds for the Central Universities of China(2018XZZX002-02,2019XZZX001-01-04,and 2019FZA7009)the National Postdoctoral Program for Innovative Talents(BX2021263).
文摘CaMKII is essential for long-term potentiation(LTP),a process in which synaptic strength is increased following the acquisition of information.Among the four CaMKII isoforms,γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons(LTPE→I).However,the molecular mechanism underlying howγCaMKII mediates LTPE→I remains unclear.Here,we show thatγCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10–30 Hz range.Following stimulation,γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95.Knocking downγCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors(AMPARs)in putative inhibitory interneurons,which are restored by overexpression ofγCaMKII but not its kinase-dead form.Taken together,these data suggest thatγCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
